Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.

实体瘤通常以酸性肿瘤微环境（TME）为特征，有利于癌症进展、治疗抵抗和免疫逃避。通过对胰腺导管腺癌 (PDAC) 个体的单细胞 RNA 测序分析，我们发现溶质载体家族 4 成员 4 (SLC4A4) 是最丰富的碳酸氢盐转运蛋白，主要由上皮导管细胞表达。从功能上讲，PDAC癌细胞中的SLC4A4抑制可减轻由于碳酸氢根在细胞外空间积聚而引起的TME酸中毒，以及由于糖酵解减少而导致癌细胞产生的乳酸减少。在携带 PDAC 的小鼠中，遗传或药理学 SLC4A4 靶向可改善 T 细胞介导的免疫反应并破坏巨噬细胞介导的免疫抑制，从而抑制肿瘤生长和转移。此外， Slc4a4靶向与免疫检查点阻断相结合能够克服免疫治疗耐药性并延长生存期。总体而言，我们的数据表明 SLC4A4 作为在 PDAC 中释放抗肿瘤免疫反应的治疗靶点。